Anti-cancer combination treatment
A cancer-resistant technology in the field of RANKL-specific inhibitors that can address issues such as increased invasion and migration
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Embodiment 1
[0230] Example 1: RANKL mediates resistance of malignant cells to chemotherapy treatment.
[0231] PBMCs (French-American-British (FAB) classification: M4; 94% peripheral blood blasts) from a patient with AML expressing RANK were subjected to a chemotherapy-resistant model ( figure 1 ). For this, patient blood was obtained at diagnosis before treatment and PBMCs were isolated by density gradient centrifugation. Observed after 48 hours of treatment by flow cytometry (PE Annexin V Apoptosis Detection Kit I, BD Pharmingen) after administration of doxorubicin (1 μM, Cytopharmaceuticals), a commonly used first-line therapy for this disease , the percentages of early apoptotic and dead cells were greatly increased compared with the control group. The effect of chemotherapy treatment was significantly reduced when sRANKL (500 ng / ml, recombinant human soluble RANKL, Immunotools, Germany) was added to the regimen, which mimics the contribution of local and systemic RANKL present in t...
Embodiment 2
[0232] Example 2: Denosumab blockade of RANKL overcomes resistance to chemotherapy treatment
[0233] Since chemotherapy resistance is a major obstacle to the success of cancer therapy, there is an urgent need to develop new therapies to overcome tumor chemoresistance, that is, to increase tumor sensitivity to antitumor drugs or chemotherapy drugs. In addition, reducing the dose of chemotherapeutics necessary to achieve adequate antitumor activity would help maintain efficacy while reducing side effects.
[0234] To this end, it was assessed whether RANKL-induced chemoresistance could be overcome by administration of a RANKL inhibitor in the form of the approved RANKL antibody denosumab. Therefore, MCF10A breast cancer cells were cultured for 48 hours in the presence or absence of sRANKL (100 ng / ml, Immunotools) and denosumab (20 μg / ml, Amgen) as indicated. After 24 hours of culture, paclitaxel (10 nM, Taxomedac), representing the first-line breast cancer therapeutic agent, w...
Embodiment 3
[0235] Example 3: Neutralization of pRANKL enhances sensitivity to chemotherapy treatment
[0236] To assess the effect of pRANKL in the context of systemic therapy, the viability of ovarian and breast cancer cells was analyzed. Cells were incubated with human platelets to neutralize pRANKL in the presence or absence of denosumab, which mimics the situation in cancer patients. The presence of platelets enhanced viability / cellular viability of tumor cells that had been treated without chemotherapy, and the same was observed when treated with chemotherapy.
[0237] Figure 4 showed that the protective effect of platelets was significantly reduced when denosumab present in the culture neutralized platelet-derived RANKL. These data suggest that targeting pRANKL resensitizes cancer cells for chemotherapy treatment. This suggests that denosumab neutralization of RANKL increases tumor cell viability, ie, chemosensitivity, after chemotherapy treatment.
[0238] The examples show p...
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